The instant invention is related to the synthesis of active principles of medicaments, specifically to the synthesis of antimycotics. Our method of synthesis consists of the manufacture of biphenylimidazolyl-(1)-phenylmethane, or (biphenyl-4yl)-imidazol-1-yl-phenylmethane, from 4-phenylbenzophenone (1). The method consists of two synthesis steps: the reduction of (I) to biphenyl-phenyl-carbinol (II) and the subsequent addition of imidazole (III) to the alcohol produced. Both synthesis steps are fast and of easy execution; the whole synthesis process does not exceed three hours. Contrary to previous methods, it does not require the use of thionyl chloride, or solvent in the synthesis process. It yields between 70 to 74% biphenylimidazolyl-(1)-phenylmethane (IV).
Bifonazole, or (biphenyl-4-yl)imidazol-1-yl-phenylmethane is a potent antimycotic, prepared for the first time by Bayer in 1974, patent granted in 1976 (Ger.Pat. 2,461,406). Since then, many modifications have been made to the same patent, all of which are registered by Bayer (U.S. Pat. No. 4,118,487).
The method of synthesis presented in Ger.Pat. 2,461,406 uses 4-phenylbenzophenone as partition reactant, and has 2 or three steps, depending on the variation of synthesis to use. One of the variations comprises the dissolution of 4-phenylbenzophenone in ethanol, then adding sodium borohydride in a 1:2 molar relation to 4-phenyl benzophenone, for the reduction of ketone to alcohol. The system is heated to reflux during fifteen hours, it is let to cool down and the reaction mixture is hydrolyzed with water acidulated with HCl, the solid obtained is purified by recrystallization in ethanol. 89% of the theoretical yield of biphenyl-phenyl-carbinol is obtained.
The second and third stage of synthesis consists of making imidazole react with thionyl chloride, using acetonitrile as solvent; the operation is performed at 10° C. To the resulting thionylbisimidazole solution, biphenyl-phenyl-carbinol is added in a 1:4 molar relation to the thionyl. After fifteen hours at room temperature, the solvent is removed by vacuum distillation. The remaining is dissolved in chloroform and washed with water, the organic phase is dried over sodium sulfate; after filtering, the solvent is vacuum distilled. The resulting solid is purified by recrystallization in acetonitrile. Bifonazole is obtained in 56% yield in relation to the theoretical.
Another variant consists of making biphenylphenylchloromethane react (product chlorated from biphenyl-phenyl-carbinol), with n-trimethylsilylimidazole dissolved in acetonitrile. The system is heated at reflux during fifteen hours, then the solvent is distilled, the residue is purified by recrystallization in ethyl acetate. Bifonazole is obtained in 56% yield in relation to the theoretical.
The German Patent 3,538,873 (1987) describes a method of synthesis for several molecules with antimycotic properties, among them Bifonazole; reacting 4-benzoylbiphenyl with imidazole in a 1:4 molar relation in p-CH3C6H4SO3H; heating the system at 180 degrees Celsius; then adding formic acid dropwise during five hours. A mixture of water-formic acid is distilled at the end of the reaction. Bifonazole is obtained in a 72.3% yield in relation to the theoretical.
Other methods use dichloromethane as solvent and add triethylamine making react biphenylphenylchloromethane with n-trimethylsilylimidazole at reflux during 5 to 10 hours; or forming n-trimethylsilylimidazole “in situ” from imidazole and CH3SiCl (Es. Patent 531,107).
Another preparation starts from cyclocondensation of 4-PhC6H4CHPhNH2, ClCH2CH2NH2HCl and HC(OEt)3 in the presence of a proton acceptor in EtOH, followed by a dehydrogenation of the resulting (biphenylbenzyl)imidazoline, which was dehydrogenated with DDQ in benzene, to yield Bifonazole (Es. Patent 549,793), no yield reported.
Bifonazole has also been prepared by benzoylation of imidazole with PhCOCl, yielding 74.7% of 1-benzoylimidazole which is subject to react with Gringnard's reactant 4-PhC6H4MgBr followed by a tosylation and subsequent reduction with sodium cyanoborohydride in hexamethylphosphoramide, to yield 68.2% Bifonazole (Es. Patent 539,345).
One can also start from imidazole, which is make to react with formic acid at 220° C. to obtain the amide; when cooling the system at 50° C., a mixture of 4-phenylbenzophenone is added in formic acid, and the system is heated at 200° C. during twenty hours, then it is stirred overnight with KOH, water and toluene to produce Bifonazole. No yield reported (East Germany DD 249,268).